Abstract: The RAS-regulated RAF?MEK?ERK MAP kinase pathway is a central pathway for pancreatic cancer initiation as 95% of pancreatic adenocarcinomas express mutationally activated KRAS. To date, however, targeting downstream components of KRAS signaling in clinical trials have not shown efficacy. Autophagy has also been shown to be important for pancreatic cancer tumorigenesis, however, clinical trials have been disappointing with chloroquine/hydroxychloroquine (4-aminoquinolones) treatment in conjunction with standard chemotherapy. We have recently demonstrated that combined inhibition of both MEK 1/2 and autophagy results in in vitro cytotoxicity and dramatic in vivo tumor regression in a recent publication in Nature Medicine, which was extended to a single pancreatic cancer patient with no therapeutic options left who demonstrated a dramatic tumor burden reduction of ~50% after 4 months of therapy of combined trametinib and hydroxychloroquine. Two Phase I/II clinical trials have resulted from the work and are either accruing or soon to open. The long-term goals of my research as a physician-scientist is to contribute a deeper mechanistic understating of KRAS signaling in pancreatic cancer and design successful clinical strategies to improve outcomes for one of the most treatment resistant human malignancies. The short-term goals of this K08 application are to understand the resistance mechanisms to trametinib and hydroxychloroquine to determine predictive biomarkers and how to overcome resistance. My immediate career goals over the next 5 years include updating and broadening my knowledge of cancer biology, becoming proficient in grant writing, accomplishing the AIMS outlined in this proposal, publishing the results, assisting in designing and executing clinical trials resulting from the work, securing grants, continued expansion of laboratory personnel, generating R01 applications, and establishing excellence in my clinical practice. My long term career goals include building an enterprise of investigations into the discovery of therapeutic targets for treating gastrointestinal malignancies, furthering the field of understanding of the role for autophagy in malignancy, and training the next generation of physicians and scientists. My mentors include Martin McMahon, PhD, G. Weldon Gilcrease III, MD and Ignacio Garrido-Laguna, MD, PhD. Dr. McMahon provides me with laboratory space and expertise in RAF?MEK?ERK MAP kinase signaling, pre-clinical modeling and pancreatic cancer cell biology. Dr. Gilcrease is a GI Oncologist provides guidance with clinical responsibilities. Dr. Garrido-Laguna is a GI Oncologist with expertise in pancreatic cancer and clinical trials, who will advise in designing and executing anticipated clinical trials that will result from this body of work. In addition to these excellent mentors in basic science and clinical pursuits I will also have the support of the Preclinical Research Resource Core and collaboration with Courtney Scaife, MD and Jill Shea, PhD who will assist with preclinical model PDX establishment and testing. In summary I will have an excellent environment to further my career with guidance and support for basic science, translational science, and clinical investigation.